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| United States Patent |
5,037,844
|
|
Hamminga
, et al.
|
August 6, 1991
|
Substituted 1H-indazole-3-carboxamides
Abstract
The present invention is concerned with compounds of formula 1:
##STR1##
wherein R.sub.1 is straight or branched alkyl having 1-4 C-atoms, halogen
or cyano;
n has the value 0-1;
R.sub.2 is hydrogen, (1-6 C)alkyl, (3-6 C)alkenyl, (3-6 C)alkenyl, (3-6
C)cycloalkyl, (3-6 C)cycloalkyl-(1-4 C) alkyl, phenyl, phenyl-(1-3
C)alkyl, COOR.sub.6, COR.sub.6, CONR.sub.6 R.sub.7 or SO.sub.2 --R.sub.6,
wherein R.sub.6 and R.sub.7 independently of each other are hydrogen, (1-6
C)alkyl, (3-6 C)cycloalkyl, phenyl or phenyl-(1-4 C)alkyl, wherein the
benzene ring is optionally substituted with a methyl group or a halogen
atom, with the proviso that R.sub.6 is not hydrogen when R.sub.2 is a
group COOR.sub.6 or SO.sub.2 R.sub.6 ;
R.sub.3 is hydrogen, straight or branched (1-6 C)alkyl or a phenyl-(1-3
C)alkyl group optionally substituted in the benzene ring; and
A is a group of formula 2 or 3
##STR2##
wherein one of the groups R.sub.8, R.sub.9 and R.sub.10 is hydrogen,
(1-C)alkyl, (3-6 C)cycloalkyl, (3-4 C)alkenyl or (3-4 C)alkynyl and the
two other groups, independently of each other, are hydrogen or (1-4
C)alkyl, and the pharmacologically acceptable acid addition salts thereof,
which are pharmaceutically useful as strong and selective antagonists of
"neuronal" 5-hydroxy tryptamine (5-HT) receptors.
| Inventors:
|
Hamminga; Derk (Weesp, NL);
van Wijngaarden; Ineke (Weesp, NL)
|
| Assignee:
|
Duphar International Research B.V. (Weesp, NL)
|
| Appl. No.:
|
554918 |
| Filed:
|
July 20, 1990 |
Foreign Application Priority Data
| Current U.S. Class: |
514/394; 548/311.7 |
| Intern'l Class: |
A61K 031/415; C07D 487/00 |
| Field of Search: |
548/327
514/394
|
References Cited
Assistant Examiner: McKane; Joseph K.
Attorney, Agent or Firm: Stevens, Davis, Miller & Mosher
Claims
We claim:
1. Compounds of formula 1:
##STR14##
wherein R.sub.1 is straight or branched alkyl having 1-4 C-atoms, halogen
or cyano;
n has the value 0-1;
R.sub.2 is hydrogen, (1-6 C)alkyl, (3-6 C)alkenyl, (3-6 C)cycloalkyl, (3-6
C)cycloalkyl-(1-4 C)alkyl, phenyl, phenyl-(1-3 C)alkyl, COOR.sub.6,
COR.sub.6, CONR.sub.6 R.sub.7 or SO.sub.2 --R.sub.6, wherein R.sub.6 and
R.sub.7 independently of each other are hydrogen, (1-6 C)alkyl, (3-6
C)cycloalkyl, phenyl or phenyl-(1-4 C)alkyl, wherein the benzene ring is
optionally substituted with a methyl group or a halogen atom, with the
proviso that R.sub.6 is not hydrogen when R.sub.2 is a group COOR.sub.6 or
SO.sub.2 R.sub.6 ;
R.sub.3 is hydrogen, straight or branched (1-6 C)alkyl or a phenyl-(1-3
C)alkyl group optionally substituted in the benzene ring; and
A is a group of formula 2 or 3
##STR15##
wherein one of the groups R.sub.8, R.sub.9 and R.sub.10 is hydrogen, (1-4
C)alkyl, (3-6 C)cycloalkyl, (3-4 C)alkenyl or (3-4 C)alkynyl and the two
other groups, independently of each other, are hydrogen or (1-4 C)alkyl,
or a pharmacologically acceptable acid addition salt thereof.
2. Pharmaceutical compositions which comprise a compound as claimed in
claim 1 as the active substance.
3. A method of treating syndromes caused by serotonin, by administering an
effective amount of a compound as claimed in claim 1.
Description
The invention relates to new 1H-indazole-3-carboxamides in which the
amide-nitrogen atom is substituted with an imidazolyl methyl group.
It is known, inter alia from European Patent Application 86302964.1
(publication no. 0.200.444) that certain indazole carboxylic acid
derivatives are 5HT-antagonists which may be used for the treatment of
serotonin-induced syndromes.
It has been found surprisingly that the new compounds of formula I
##STR3##
wherein R.sub.1 is halogen, cyano or straight or branched alkyl having 1-4
C-atoms;
n has the value 0-1;
R.sub.2 is hydrogen, (1-6 C)alkyl, (3-6 C)alkenyl, (3-6 C)alkynyl, (3-6
C)cycloalkyl, (3-6 C)cycloalkyl-(1-4 C)alkyl, phenyl, phenyl-(1-3 C)alkyl,
COOR.sub.6, COR.sub.6, CONR.sub.6 R.sub.7 or SO.sub.2 --R.sub.6, wherein
R.sub.6 and R.sub.7 independently of each other are hydrogen, (1-6
C)alkyl, (3-6 C)cycloalkyl, phenyl or phenyl-(1-4 C)alkyl, wherein the
benzene ring is optionally substituted with a methyl group or a halogen
atom, with the proviso that R.sub.6 is not hydrogen when R.sub.2 is a
group COOR.sub.6 or SO.sub.2 R.sub.6 ;
R.sub.3 is hydrogen, straight or branched (1-6 C)alkyl or a phenyl-(1-3
C)alkyl group optionally substituted in the benzene ring; and
A is a group of formula 2 or 3
##STR4##
10 wherein one of the groups R.sub.8, R.sub.9 and R.sub.10 is hydrogen
(1-4 C)alkyl, (3-6 C)cycloalkyl. (3-4 C)alkenyl or (3-4 C)alkynyl and both
other groups, independently of each other, are hydrogen or (1-4 C)alkyl,
and the pharmacologically acceptable acid addition salts thereof are very
strong and selective antagonists of "neuronal" 5-hydroxytryptamine (5-HT)
receptors.
Preferred embodiments of the invention are the compounds of formula (1)
wherein R.sub.3 is a (1-6 C)alkyl group.
Preferred embodiments of the invention are also the compounds of formula
(1) wherein the groups R.sub.8, R.sub.9 and R.sub.10 have the meanings:
hydrogen or (1-4 C)alkyl.
Suitable acids with which the compounds of formula I according to the
invention can form pharmaceutically acceptable acid addition salts are,
for example, hydrochloric acid, sulphuric acid, phosphoric acid, nitric
acid, and organic acids, for example citric acid, fumaric acid, maleic
acid, tartaric acid, acetic acid, benzoic acid, p-toluene sulphonic acid,
methane sulphonic acid and the like.
The racemates as well as (geometric) isomers and the individual enantiomers
of compounds of formula 1 belong to the invention.
The antagonistic activity of the compounds of formula 1 on the response
induced by 5-HT or 2-methyl-5-HT was determined and measured in the
Bezold-Jarish reflex test in rats. The affinity to "neuronal"
5-HT-receptors was determined and measured by the displacement of (.sup.3
H)GR 38032F from neuroblastoma cells.
On the basis of the antagonistic effect on this type of 5-HT-receptors, the
compounds may be used for the treatment of symptoms which are caused by
overexcitation of the said receptors a) in the gastrointestinal system
(nausea and vomiting as a result of exogenic factors, for example, cancer
therapy, or endogenic factors, for example, stasis of the stomach and
migraine), ulcer, dyspepsia, spasms, irritable bowel syndrome, etc., or b)
in the central nervous system (hallucinations, delusions, manias,
depressions, anxiety, pain, nausea, improvement of vigility, etc., or c)
in the cardiovascular system, for example, spasms of the vessels,
arrhythmia, etc., or d) in the respiratory system (including nasal
disturbances and disturbances of bronchi and lungs, or e) for relieving or
preventing withdrawal symptoms which are induced by drug abuse.
The compounds according to the invention and their salts may be brought
into forms suitable for administration, for example, pills, tablets,
coated tablets, capsules, powders, injection liquids and the like, by
means of the techniques conventionally used for this purpose and while
using suitable auxiliary substances, for example, solid or liquid carrier
materials.
The dosage in which the compounds according to the invention may be used
depend on the severity and the nature of the disease to be treated and on
the way of administration. As a rule, the dosage will be between 0.05 and
20 mg, preferably between 0.1 and 10 mg of active substance daily.
The compounds according to the invention may be prepared in a manner known
per se for analogous compounds, for example:
a) by reaction of a compound of formula 4
##STR5##
wherein R.sub.1, R.sub.2 and n have the meanings given in formula 1 and
wherein X is a group which may be replaced by a nucleophile, for example,
a halogen atom, with a compound of formula 5
##STR6##
wherein R.sub.3 and A have the meanings given in formula 1, or wherein A
is a group which after splitting off a protecting group provides a group A
which has the meaning mentioned in formula 1.
The reaction is preferably carried out in a suitable solvent, for example,
acetonitrile, dimethyl formamide, methylene chloride, etc., in the
presence of a base, for example, triethylamine, pyridine, etc., at
temperatures between 0.degree. and 100.degree. C.
The compounds of formula 6
##STR7##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.8, R.sub.10, and n have the
meanings mentioned in formula 1, can be obtained in particular in good
yield by reaction of a compound of formula 4 with a compound of formula 7
or 8
##STR8##
and then removing the trityl group form the resulting reaction product,
for example, in acid conditions or with palladium on carbon and ammonium
formiate, preferably in a suitable solvent; or
b) by reaction of a compound of formula 9
##STR9##
wherein R.sub.1, R.sub.3, n and A have the meanings mentioned in formula 1
(with the proviso that R.sub.9 in group A is not a hydrogen atom) and M is
an alkali metal atom, with a compound of the formula R.sub.2 --X, wherein
R.sub.2 has the meaning mentioned in formula 1 and X is a group which may
be replaced by a nucleophile, for example, an iodine atom. The reaction is
preferably carried out in a solvent, for example, acetonitrile, dimethyl
formamide, etc., at temperatures between 0.degree. and 150.degree. C.; or
c) by reaction of a compound of formula 10 or 11
##STR10##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.8, R.sub.10, and n have the
meanings mentioned in formula 1 and M is an alkali metal atom with a
compound of the formula R.sub.9 --X, wherein R.sub.9 has the meaning
mentioned in formula 1 and X is a group which may be replaced by a
nucleophile, for example, a halogen atom.
The invention will be described in greater detail with reference to the
following specific examples.
EXAMPLE
N-methyl-N-[(4-methyl-1H-imidazol-5-yl)methyl]-1
methyl-1H-indazole-3-carboxamide hydrochloride
1.4 g (7.96 mmol) of 1-methyl-1H-indazole-3-carboxylic acid were dissolved
in 50 ml of chloroform. 1.7 ml (24 mmol) of thionyl chloride were added
and the mixture was boiled for 1 hour. It was then evaporated in vacuo.
Chloroform was added and the mixture was again evaporated in vacuo. The
residue was dissolved in 40 ml of methylene chloride, after which 1.2 ml
(8.7 mmol) of triethyl amine and 2.92 g (7.96 mmol) of the mixture of
N-methyl-N-[(4-methyl-1-triphenylmethyl-1H-imidazol-5-yl)methyl]-amine and
N-methyl-N-[(5-methyl-1-triphenylmethyl-1H-imidazol-4-yl)methyl]-amine in
20 ml of methylene chloride were added. The mixture was stirred at room
temperature for 30 minutes. The reaction mixture was then shaken with
water. The methylene chloride solution was washed with water, dried and
evaporated in vacuo. The residue was chromatographed over silica gel using
methylene chloride/ethanol (95/5) as an eluent. 2.1 g of the isomer
mixture of N-methyl-N-[(4(or 5)-methyl-1 triphenylmethyl-1H-imidazol-5 (or
4)-yl)methyl]-1-methyl-1H-indazole-3-carboxamide were obtained.
The isomer mixture thus obtained (2.1 g) was brought in a mixture of 50 ml
of acetic acid and 50 ml of water and boiled for 1 hour. The mixture was
then evaporated in vacuo. The residue was shaken with 2N sodium hydroxide
solution and with methylene chloride. The methylene chloride layer was
separated and evaporated in vacuo, after which the residue was
chromatographed over silica gel using methylene chloride/methanol/ammonia
(92/7.5/0.5) as an eluent. The good fractions were evaporated. The residue
was dissolved in ethyl acetate and alcoholic hydrochloric acid was then
added. After sucking off the solid, 1.0 g of the desired hydrochloride was
obtained having a melting point of 193.degree.-194.degree. C. .sup.13 C
NMR(CDCl.sub.3, Ref.: TMS, Additive: Triethyl amine):
______________________________________
##STR11##
______________________________________
1 140.50 S 6 127.22
D # 11 45.31
T
2 138.08 S 7 109.14
D 12 133.87
D
3 124.13 S 8 36.77
Q 13 130.64
S
4 122.47 D # 9 164.35
S 14 126.90
S
5 122.23 D # 10 36.01
Q 15 10.82
Q
1 140.31 S 6 126.77
D # 11 42.70
T
2 137.96 S 7 109.14
D 12 133.39
D
3 124.10 S 8 36.01
Q 13 129.28
S
4 122.29 D # 9 163.58
S 14 125.35
S
5 122.12 D # 10 32.94
Q 15 10.62
Q
______________________________________
Mixture of 2 amide isomers; Chemical shifts are exchangeable. Some lines
are broad.
In a analogous manner were obtained:
1.
N-methyl-N-{(4-methyl-1H-imidazol-5-yl)methyl}-1-allyl-1H-indazole-3-carbo
xamide; melting point 142.degree.-143.degree. C.
.sup.13 C NMR (CDCl.sub.3, Ref.: TMS):
______________________________________
##STR12##
______________________________________
1 139.85 S 7 109.34
D 13 42.97
T
2 138.43 S 8 51.84
T 14 133.57
D
3 124.28 S 9 132.18
D 15 129.00
4 122.41 D # 10 117.97
T 16 125.40
5 122.12 D # 11 163.55
S 17 10.61
Q
6 126.72 D # 12 32.90
Q
1 140.13 S 7 109.34
D 13 45.39
T
2 138.56 S 8 51.96
T 14 133.83
D
3 124.28 S 9 132.18
D 15 130.90
4 122.52 D # 10 118.63
T 16 127.60
5 122.32 D # 11 164.15
S 17 10.92
Q
6 127.25 D # 12 36.65
Q
______________________________________
Mixture of 2 amide isomers; C.S. are exchangeable. Some lines are broad.
2.
N-methyl-N-{(4-methyl-1H-imidazol-5-yl)methyl}-1-allyl-7-fluoro-1H-indazol
e-3-carboxamide
.sup.13 C NMR (CDC.sub.3, Ref.: TMS):
______________________________________
##STR13##
______________________________________
1 129.44 S 7 148.12
S 13 43.04
T
2 138.94 S 8 54.17
T 14 133.66
D
3 128.00 S 9 132.72
D 15 130.47
S
4 118.24 D 10 117.96
T 16 123.90
S
5 122.72 D 11 162.86
S 17 11.02
Q
6 111.51 D 12 32.95
Q *.00
COUPLING CONSTANTS:
J(7,F18) = 247.8
J(6,F18) = 17.4
J(1,F18) = 13.1
J(5,F18) = 5.8
J(4,F18) = 4.4
J(3,F18) = 3.6
1 129.82 S 7 148.17
S 13 45.04
T
2 139.39 S 8 54.21
T 14 133.96
D
3 128.19 S 9 132.78
D 15 132.60
S
4 118.53 D 10 118.79
T 16 126.21
S
5 123.02 D 11 163.98
S 17 11.34
Q
6 112.14 D 12 36.98
Q *.00
COUPLING CONSTANTS:
J(7,F18) = 247.8
J(6,F18) = 17.4
J(1,F18) = 12.4
J(5,F18) = 5.1
J(4,F18) = 4.4
J(3,F18) = 2.9
______________________________________
Mixture of 2 amide isomers; C.S. are exchangeable. Some lines are broad.
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